Mental Health: 1 in 3 people experience debilitating anxiety

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According to the National Institute of Mental Health, 1 in 3 people experience debilitating anxiety–the kind that prevents someone from going about their normal life. Women are also more at risk to suffer from anxiety.

Yet the roots of anxiety and other anxiety-related diseases, such as Obsessive-Compulsive Disorder (OCD), are still unclear.

In a new study, University of Utah scientists discovered a new lineage of specialized brain cells, called Hoxb8-lineage microglia, and established a link between the lineage and OCD and anxiety in mice.

Mice with disabled Hoxb8-lineage microglia exhibited excessive overgrooming behavior.

The symptom resembles behavior in humans with a type of OCD called trichotillomania, a disorder that causes people to obsessively pluck out their own hair.

Their experiments proved that Hoxb8-lineage microglia prevent mice from displaying OCD behaviors.

Additionally, they found that female sex hormones caused more severe OCD behaviors and induced added anxiety in the mice.

“More women than men experience debilitating anxiety at some point in their lives. Scientists want help these people to get their lives back. In this study were able to link anxiety to a dysfunction in a type of microglia, and to female sex hormones,” said lead author Dimitri Traenkner, research assistant professor in the School of Biological Sciences at the University of Utah.

“It opens up a new avenue for thinking about anxiety. Since we have this model, we have a way to test new drugs to help these mice and hopefully at some point, this will help people.”

The study published today in Cell Reports.

Discovery of a new microglia lineage

Microglia are crucial during brain development in the womb–they ensure that brain structures and neural circuitry all wire together correctly.

Traenkner and colleagues showed that microglia belong to least two distinct sub-lineages of cells.

One lineage called Hoxb8-lineage microglia makes up about 30% of all microglia in the brain but until now, no one knew whether they had any unique function.

Mario Capecchi, Nobel laureate and senior author of the study, had long suspected that Hoxb8-microglia were special.

In previous research, he disabled Hoxb8-lineage microglia expecting some impact on development. But the mice seemed fine.

‘We didn’t really know what to make of the fact that mice without Hoxb8 appear so normal, until we noticed that they groom significantly more and longer than what would be considered healthy.

And that’s how the whole thing started,” said Capecchi, who is also a distinguished professor of human genetics at the University of Utah Health.

This is the first study to describe microglia’s role in OCD and anxiety behaviors in mice.

According to the National Institute of Mental Health, 1 in 3 people experience debilitating anxiety–the kind that prevents someone from going about their normal life. Women are also more at risk to suffer from anxiety. Yet the roots of anxiety and other anxiety-related diseases, such as Obsessive Compulsive Disorder (OCD), are still unclear.

“Researchers have long suspected that microglia have a role in anxiety and neuropsychological disorders in humans because this cell type can release substances that may harm neurons. So, we were surprised to find that microglia actually protect from anxiety, they don’t cause it,” added Traenkner.

Female sex hormones drive symptom severity

The mice showed sex-linked severity in their symptoms; female mice’s OCD symptoms were consistently more dramatic than in the males.

Females also exhibited an additional anxiety symptom that was lacking in male mice–the researchers designed and validated a new test showing that the pupils of female mice dilated dramatically, triggered by a fight-or-flight stress response.

To test whether sex hormones drove OCD and anxiety symptoms, Traenkner and colleagues manipulated estrogen and progesterone levels in the mice.

They found that at male-levels, female mice’s OCD and anxiety behaviors resembled the male response, and at female hormone levels, male mice’s OCD behaviors looked more like the female’s severe symptoms, and showed signs of anxiety.

“Our findings strongly argue for a mechanistic link between biological sex and genetic family history in the risk to develop an anxiety disorders,” said Traenkner.

What does this mean for humans?

For many, anxiety drastically impacts their work, friends, family and lifestyle. Scientists and health care professionals are always looking for ways to help people get their lives back. This study of mouse models links anxiety to dysfunctional microglia.

Down the line, the findings could spark new microglia-focused studies in patients with anxiety and, eventually, help to better treat this debilitating disorder.

“It’s not that we discovered how to fix anxiety in humans, but we constructed a platform for the discovery of new drugs against anxiety,” Traenkner said.


Characteristic Symptoms Pathological Anxiety

Cognitive symptoms: fear of losing control; fear of physical injury or death; fear of “going crazy”; fear of negative evaluation by others; frightening thoughts, mental images, or memories; perception of unreality or detachment; poor concentration, confusion, distractible; narrowing of attention, hypervigilance for threat; poor memory; and difficulty speaking.

Physiological symptoms: increased heart rate, palpitations; shortness of breath, rapid breathing; chest pain or pressure; choking sensation; dizzy, light-headed; sweaty, hot flashes, chills; nausea, upset stomach, diarrhea; trembling, shaking; tingling or numbness in arms and legs; weakness, unsteadiness, faintness; tense muscles, rigidity; and dry mouth.

Behavioral symptoms: avoidance of threat cues or situations; escape, flight; pursuit of safety, reassurance; restlessness, agitation, pacing; hyperventilation; freezing, motionless; and difficulty speaking.

Affective symptoms: nervous, tense, wound up; frightened, fearful, terrified; edgy, jumpy, jittery; and impatient, frustrated.

Anxiety Disorders as defined in the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM–5; American Psychiatric Association, 2013):

  • Separation Anxiety Disorder: An individual with separation anxiety disorder displays anxiety and fear atypical for his/her age and development level of separation from attachment figures. There is persistent and excessive fear or anxiety about harm to, loss of, or separation from attachment figures. The symptoms include nightmares and physical symptoms. Although the symptoms develop in childhood, they can be expressed throughout adulthood as well.
  • Selective Mutism: This disorder is characterized by a consistent failure to speak in social situations where there is an expectation to speak even though the individual speaks in other circumstances, can speak, and comprehends the spoken language. The disorder is more likely to be seen in young children than in adolescents and adults.
  • Specific Phobia: Individuals with a specific phobia are fearful or anxious about specific objects or situations which they avoid or endure with intense fear or anxiety. The fear, anxiety, and avoidance is almost always immediate and tends to be persistently out of proportion to the actual danger posed by the specific object or situation. There are different types of phobias: animal, blood-injection-injury, and situational.
  • Social Anxiety Disorder: This disorder is characterized by marked or intense fear or anxiety of social situations in which one could be the subject of scrutiny. The individual fears that he/she will be negatively evaluated in such circumstances. He/she also fears being embarrassed, rejected, humiliated or offending others. These situations always provoke fear or anxiety and are avoided or endured with intense fear and anxiety.
  • Panic Disorder: Individuals with this disorder experience recurrent, unexpected panic attacks and experience persistent concern and worry about having another panic attack. They also have changes in their behavior linked to the panic attacks which are maladaptive, such as avoidance of activities and situations to prevent the occurrence of panic attacks. Panic attacks are abrupt surges of intense fear or extreme discomfort that reach a peak within minutes, accompanied by physical and cognitive symptoms such as palpitations, sweating, shortness of breath, fear of going crazy, or fear of dying. Panic attacks can occur unexpectedly with no obvious trigger, or they may be expected, such as in response to a feared object or situation.
  • Agoraphobia: Individuals with this disorder are fearful and anxious in two or more of the following circumstances: using public transportation, being in open spaces, being in enclosed spaces like shops and theaters, standing in line or being in a crowd, or being outside of the home alone. The individual fears and avoids these situations because he/she is concerned that escape may be difficult or help may not be available in the event of panic-like symptoms, or other incapacitating or embarrassing symptoms (e.g., falling or incontinence).
  • Generalized Anxiety Disorder: The key feature of this disorder is persistent and excessive worry about various domains, including work and school performance, that the individual finds hard to control. The person also may experience feeling restless, keyed up, or on edge; being easily fatigued; difficulty concentrating or mind going blank; irritability, muscle tension, and sleep disturbance.
  • Substance/Medication-Induced Anxiety Disorder: This disorder involves anxiety symptoms due to substance intoxication or withdrawal or to medical treatment.
  • Anxiety Disorder Due to Other Medical Conditions: Anxiety symptoms are the physiological consequence of another medical condition. Examples include endocrine disease: hypothyroidism, hypoglycemia, and hypercortisolism; cardiovascular disorders: congestive heart failure, arrhythmia, and pulmonary embolism; respiratory illness: asthma and pneumonia; metabolic disturbances: B12 or porphyria; neurological illnesses: neoplasms, encephalitis, and seizure disorder.

Evaluation

When the history and examination do not suggest the symptoms as arising from any other medical disorder, the initial laboratory studies may be limited to the following: complete blood cell count (CBC) chemistry profile, thyroid function tests, urinalysis, and urine drug screen.[5][6][7]

If the anxiety symptoms are atypical or there are some abnormalities noted in the physical examination more detailed evaluations may be indicated to identify or exclude underlying medical conditions. This would include the following: electroencephalography, brain computed tomography (CT) scan, electrocardiography, tests for infection, arterial blood gas analysis, chest radiography, and thyroid function tests.

Treatment / Management

Treatment consists of psychotherapy, pharmacotherapy, or a combination of both.

Pharmacotherapy: selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), benzodiazepines, tricyclic antidepressants, mild tranquilizers, and beta-blockers treat anxiety disorders. [3][8][9]

  • SSRIs (fluoxetine, sertraline, paroxetine, escitalopram, and citalopram) are an effective treatment for all anxiety disorders and considered first-line treatment.
  • SNRIs (venlafaxine and duloxetine) are considered as effective as SSRIs and also are considered first-line treatment, particularly for generalized anxiety disorder (GAD).
  • Tricyclic antidepressants (amitriptyline, imipramine, and nortriptyline) are useful in the treatment of anxiety disorders but cause significant adverse effects.
  • Benzodiazepines (alprazolam, clonazepam, diazepam, and lorazepam) are used for short-term management of anxiety. They are fast acting and bring relief within 30 minutes to an hour. They are effective in promoting relaxation and reducing muscular tension and other symptoms of anxiety. Because they work quickly, they are effective when taken for panic attacks or overwhelming episodes. Long-term use may require increased doses to achieve the same effect, which may result in problems related to tolerance and dependence.
  • Buspirone is a mild tranquilizer that is slow acting as compared to benzodiazepines and takes about 2 weeks to start working. It has the advantage of being less sedating and also not being addicting with minimal withdrawal effects. It works for GAD.
  • Beta-blockers (propranolol and atenolol) control the physical symptoms of anxiety such as rapid heart rate, a trembling voice, sweating, dizziness, and shaky hands. They are most helpful for phobias, particularly social phobia.

Psychotherapy: One of the most effective forms of psychotherapy is cognitive-behavioral therapy. It is a structured, goal-oriented, and didactic form of therapy that focuses on helping individuals identify and modify characteristic maladaptive thinking patterns and beliefs that trigger and maintain symptoms. This form of therapy focuses on building behavioral skills so that patients can behave and react more adaptively to anxiety-producing situations. Exposure therapy is utilized to move individuals towards facing the anxiety-provoking situations and stimuli which they typically avoid. This exposure results in a reduction in anxiety symptoms as they learn that their anxiety is causing them to experience false alarms and they do not need to fear the situation or stimuli and can cope effectively with such a situation.

Pearls and Other Issues

Characteristic features noted in individuals with clinical anxiety:

  1. False alarms: The presence of intense fear in the absence of threat cues or very minimal threat provocation.
  2. Persistence: There is a future-oriented perspective that involves the anticipation of threat or danger which causes the patient to experience a heightened level of apprehension and thoughts about impending potential threat, regardless of whether it materializes.
  3. Impaired Functioning: The anxiety interferes with effective and adaptive coping in the face of a perceived threat and the person’s daily social or occupational life.
  4. Stimulus hypersensitivity: In clinical states, fear is elicited by a wider range of stimuli or situations of relatively mild intensity that would be innocuous to a person who does not have clinical anxiety.
  5. Dysfunctional cognition and cognitive symptoms: Thinking characterized by overestimation of threat or danger appraisal of a situation that is not confirmed in any way.

Enhancing Healthcare Team Outcomes

Anxiety disorders are very common and can present in diverse ways. When a person has chronic anxiety, the condition can be very debilitating and hence it is best managed by a multidisciplinary team consisting of a mental health nurse, psychiatrist, psychotherapist, social worker, and a primary care provider. The outlook for patients with anxiety is guarded. Data indicate that the high rates of mortality are associated with adverse cardiac events. In those with social phobia, the condition leads to significant functional impairment and a very poor quality of life. The risk of suicides is also high in this population. Patients with anxiety need lifelong follow up because, despite drug therapy, relapse rates are high. [2][10][11](Level V)


Source:
University of Utah
Media Contacts:
Lisa Potter – University of Utah
Image Source:
The image is credited to Ann Martin.

Original Research: Closed access
“A Microglia Sublineage Protects from Sex-Linked Anxiety Symptoms and Obsessive Compulsion”. Dimitri Traenkner et al.
Cell Reports doi:10.1016/j.celrep.2019.09.045.

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